A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy
A major challenge of current leprosy control is the management of host pathological immune responses coined Type-1 Reactions (T1R). T1R are characterized by acute inflammatory episodes whereby cellular immune responses are directed against host peripheral nerve cells. T1R affects up half of all lepr...
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| Format: | Online |
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Public Library of Science
2016
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742274/ |
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pubmed-47422742016-02-11 A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy Fava, Vinicius M. Manry, Jérémy Cobat, Aurélie Orlova, Marianna Van Thuc, Nguyen Ba, Nguyen Ngoc Thai, Vu Hong Abel, Laurent Alcaïs, Alexandre Schurr, Erwin Research Article A major challenge of current leprosy control is the management of host pathological immune responses coined Type-1 Reactions (T1R). T1R are characterized by acute inflammatory episodes whereby cellular immune responses are directed against host peripheral nerve cells. T1R affects up half of all leprosy patients and are a major cause of leprosy-associated disabilities. Since there is evidence that host genetic factors predispose leprosy patients to T1R, we have conducted a candidate gene study to test if LRRK2 gene variants are T1R risk factors. The choice of LRRK2 was motivated by the fact that LRRK2 was associated with leprosy per se in some but not in other studies. We reasoned that this may reflect different proportions of leprosy patients with T1R in the different samples and that LRRK2 may in truth be a T1R susceptibility gene. Here, we show that variants overlapping the LRRK2 gene, reported as suggestive leprosy per se susceptibility factors in a previous genome-wide association study, are preferentially associated with T1R. The main SNP carrying most of the association signal is the amino-acid change M2397T (rs3761863) which is known to impact LRRK2 turnover. Interestingly, eQTL SNPs counterbalanced the effect of the M2397T variant but this compensatory mechanism was abrogated by Mycobacterium leprae antigen stimulation. Public Library of Science 2016-02-04 /pmc/articles/PMC4742274/ /pubmed/26844546 http://dx.doi.org/10.1371/journal.pntd.0004412 Text en © 2016 Fava et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Fava, Vinicius M. Manry, Jérémy Cobat, Aurélie Orlova, Marianna Van Thuc, Nguyen Ba, Nguyen Ngoc Thai, Vu Hong Abel, Laurent Alcaïs, Alexandre Schurr, Erwin |
| spellingShingle |
Fava, Vinicius M. Manry, Jérémy Cobat, Aurélie Orlova, Marianna Van Thuc, Nguyen Ba, Nguyen Ngoc Thai, Vu Hong Abel, Laurent Alcaïs, Alexandre Schurr, Erwin A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy |
| author_facet |
Fava, Vinicius M. Manry, Jérémy Cobat, Aurélie Orlova, Marianna Van Thuc, Nguyen Ba, Nguyen Ngoc Thai, Vu Hong Abel, Laurent Alcaïs, Alexandre Schurr, Erwin |
| author_sort |
Fava, Vinicius M. |
| title |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy |
| title_short |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy |
| title_full |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy |
| title_fullStr |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy |
| title_full_unstemmed |
A Missense LRRK2 Variant Is a Risk Factor for Excessive Inflammatory Responses in Leprosy |
| title_sort |
missense lrrk2 variant is a risk factor for excessive inflammatory responses in leprosy |
| description |
A major challenge of current leprosy control is the management of host pathological immune responses coined Type-1 Reactions (T1R). T1R are characterized by acute inflammatory episodes whereby cellular immune responses are directed against host peripheral nerve cells. T1R affects up half of all leprosy patients and are a major cause of leprosy-associated disabilities. Since there is evidence that host genetic factors predispose leprosy patients to T1R, we have conducted a candidate gene study to test if LRRK2 gene variants are T1R risk factors. The choice of LRRK2 was motivated by the fact that LRRK2 was associated with leprosy per se in some but not in other studies. We reasoned that this may reflect different proportions of leprosy patients with T1R in the different samples and that LRRK2 may in truth be a T1R susceptibility gene. Here, we show that variants overlapping the LRRK2 gene, reported as suggestive leprosy per se susceptibility factors in a previous genome-wide association study, are preferentially associated with T1R. The main SNP carrying most of the association signal is the amino-acid change M2397T (rs3761863) which is known to impact LRRK2 turnover. Interestingly, eQTL SNPs counterbalanced the effect of the M2397T variant but this compensatory mechanism was abrogated by Mycobacterium leprae antigen stimulation. |
| publisher |
Public Library of Science |
| publishDate |
2016 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742274/ |
| _version_ |
1613534193197776896 |